Pyrazinylmalonic acid esters and salts and pyrazinylacetic acids, esters and salts

ABSTRACT

The compound, 2,3-diphenyl-5-ethylpyrazine, useful as a precursor in the synthesis of those compounds of the class of pyrazine, arylpyrazine, diphenylpyrazine, and cycloalkylpyrazine malonates, acetates, acetamides, and acetic acids, useful for their ultraviolet light absorption properties.

United States Patent [191 Schwartz et a1.

[ PYRAZINYLMALONIC ACID ESTERS AND SALTS AND PYRAZINYLACETIC ACIDS,

ESTERS AND SALTS [75] Inventors: Norman Schwartz, Philadelphia;

Richard J. Mohrbacher, Fort Washington, both of Pa.

[73] Assignee: McNeil Laboratories, Incorporated,

Fort Washington, Pa.

[22] Filed: Nov. 17, 1972 [21] Appl. No.: 307,682

Related U.s. Application Data [62] Division of Ser. No. 774,486, Nov. 8, 1968, Pat. No.

[52] US. Cl. 260/250 B; 424/250 [51] Int. Cl. C07D 241/02 Dec. 23, 1975 [58] Field of Search 260/250 B [56] References Cited UNITED STATES PATENTS 3,006,918, 10/1961 de Jongh et a1. 260/250 Primary Examiner-Nicholas S. Rizzo Attorney, Agent, or Firm-Salvatore R. Conte 4 Claims, No Drawings PYRAZINYLMALONICACID ESTERS AND SALTS AND PYRAZINYLACETIC ACIDS, ESTERS AND SALTS This is a divisional application .of my co-pending application Ser. No.- 774,486,;filed Nov. ;8-,.l968 now issued as US. Pat. No. 3,76l,477. x x Y This invention relates to certain novel: pyrazineacetic acids, acetates, and acetamides. More particularly, this invention is concerned with arylpyrazine and cycloalkylpyrazine malonates, acetates,,acetamides, and acetic acids having the formulae wherein R is a member selected from the group consisting of phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, trifluoromethylphenyl, loweralkoxyphenyl, diloweralkoxyphenyl, loweralkylphenyl, diloweralkylphenyl, cyclohexyl and cyclopentyl; R, is a member selected from the group consisting of hydrogen and loweralkyl; R is a member of the group consisting of hydrogen, loweralkyl, loweralkyl carboxylate ester, and sodium,calcium, and ammonium carboxylate salts; and X is a member selected from the group consisting of loweralkyl carboxylate ester, carboxylic acid, carbox- 3 amide, a member selected from the group consisting of N-loweralkyl-, N,N-diloweralkyl, N-aryl-, N-aralkyl-, and N-heterocyclie-substituted carboxamides, and sodium, calcium and ammonium carboxylate salts; wherein, when R is respectively'loweralkyl carboxylate ester or carboxylate salt, X is also respectively loweralkyl carboxylate ester or carboxylate salt.

This invention is also concerned with pyrazine malonates, acetates, and acetic acids having the formula:

wherein R, is a member selected from the group consisting of hydrogen and loweralkyl; R is a member wherein R is a member selected from the group consisting of hydrogen and loweralkyl; R is a member selected from the group consisting of hydrogen, loweralkyl, loweralkyl carboxylate ester, and sodium, calcium, and ammonium carboxylate salts; X is a member selected from the group consisting of loweralkyl carboxylate ester, carboxylic acid, carboxamine, a member selected from the group consisting of N-loweralkyl- -N,Ndiloweralkyl, N-aryl-, N-aralkyl-, and N- heterocyclio-substituted carboxamides, and sodium. calcium, and ammonium carboxylate salts; and wherein when R is respectively loweralkyl carboxylate ester or carboxylate salt, X is also respectively loweralkyl carboxylate ester or carboxylate salt.

The term loweralkyl includes alkyl groupscontaining 1 to 7 carbon atoms, and preferably 1 .to 4 carbon atoms, including saturated aliphatic chains, straight or branched, such as. methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl. 4 y v The compounds of this invention absorb ultraviolet light and are useful as sun-screening materials in salves and ointments. in addition, because of their solubility in organic materials generally, they may be used as ultraviolet absorbers in plastics and resins, such as polystyrene, polyethylene, polypropylene, polyacrylics (methacrylate resins, polyacylamides, polyacrylonitrile fibers), polyamide fibers (nylon e.g.), and polyester fibers. In the latter use, the inclusion of 0.01 to 5 percent of the absorber, based on the polymer weight, is sufficient to render protection against ultraviolet light, such as in plastic film or light filters. The absorber may be incorporated in the mixtures of monomers before polymerization to form the polymer or it may be incorporated in the polymer at any stage during its handling, as by milling into the polymer together with other compounding ingredients or during the spinning of polymers into fibers, etc.

Due to the asymmetric center present in the subject compounds wherein R, and R are different, except where R is identical with X or Z, it is evident that the existence of such compounds in the form of resolved enantiomorphs is possible. It is naturally intended that such enantiomorphs are included within the scope of this invention.

Compounds of Formula I and Formula II, wherein R, is hydrogen or loweralkyl, R is loweralkyl carboxylate, and X or Z is loweralkyl carboxylate are prepared by reacting the appropriate 2-chloropyrazine derivative with diloweralkyl malonate or diloweralkyl loweralkylmalonate in the presence of sodium hydride in a suitable solvent such as dimethylformamide. As an alternative process, sodamide and liquid ammonia may be employed in place of sodium hydride and dimethylformamide.

Compounds of Formula I and Formula ll wherein R,- and R are both hydrogen or R, is hydrogen and'R is loweralkyl and X or Z is loweralkyl carboxylate are- 5 prepared by heating the foregoing diloweralkyl pyrazinylmalonate and diloweralkyl a-loweralkylpyrazinyh' 3 pyrazineacetic acid derivatives-may be prepared by treating the diloweralkyl pyrazinylmalonates and the diloweralkyl a-loweralkylpyrazinylmalonates of Formula l and Formula ll with a base such as aqueous sodium hydroxide, and thereafter acidifying the solution.

Compounds of Formula I wherein X is carboxamide are prepared by reacting the aforesaid pyrazineacetate are a-loweralkylpyrazineacetate derivatives with ammonium hydroxide.

in an alternative procedure, loweralkyl esters of the acetic acids of Formula I and Formula II may be prepared from the corresponding acids by conventional esterification procedures. in another alternative procedure, the acetamides of Formula I may be reacted with aqueous hydrochloric acid, avoiding excess temperatures, or with sodium or ammonium hydroxide and thereafter, acidifying to form the corresponding pyrazineacetic acid derivatives.

Compounds of Formula I and ll wherein R and R 55 are each loweralkyl and X or Z are loweralkyl carboxylate are prepared by reacting a loweralkyl halide, such as methyl, ethyl, isopropyl or n-butyl iodide, with the aforementioned loweralkyl a-loweralkylpyrazineacetates in the presence of sodamide in liquid ammonia.

boxylate' may be converted to the corresponding acetamides and acetic acids by the procedures described hereinhefore for the compounds wherein R is loweralkyl and R is hydrogen.

The N-substituted acetamides of this invention may be prepared by reacting the corresponding acetic acid derivatives of this invention with thionyl chloride and then with the desired amine.

The salts of the acetic acid derivatives of this invention may be prepared by reacting the corresponding acid in water with sodium, calcium, or ammonium hydroxide.

Compounds of the Formula III are prepared in the same manner as in the case of compounds of Formula I and Formula ll, using 5,-chloro-2,3-diphenylpyrazine as the starting material. i

The following schematic diagram, exemplifying the preparation of Formula I type compounds, illustrates the foregoing syntheses:

R 1 I "g', CHCOO New on: anally R v N thionyl chloride;

R c ticoun'a" H CHCOCI NHR'R" R loweralkyl amines hetero amines, N or etdllty amines (mono-- or di substitution) The following schematic diagram illustrates the preparation of the starting materials used in the synthesis of the novel compounds of this invention:

H2" 0 H2O Hcl a *0 NuOH - Continued H 2" CONH NuHSO CONH a R N cl N Cl POCI I pressure and heat N R Except when R is cyclohexyl.

. qr CHCOBr cu cooi-i v B 2 a PB r NH3 NGOH POCI I pressure and heat N The following examples are intended to illustrate, but not to limit, the scope of the present invention.

' EXAMPLE I To a mixture of phenylglyoxal hydrate (41.5 g., 0.27 mole) in 250 ml. of methanol at 40 (dry ice-carbon tetrachloride-acetone) is added, with stirring, glycinamide hydrochloride (30.0 g., 0.27 mole) in 250 ml. of methanol, precooled to 40 C. To this stirred mixture 50 ml. of 12.5 N sodium hydroxide is added dropwise while the temperature is maintained at -30 C. The

temperature is raised to between 20 and -l0 for /2 hour, to 0 for 2 hours, and finally to room temperature for 2 hours. The reaction mixture is then cooled in an ice-bath and treated dropwise with 45 ml. of concentrated hydrochloric acid. The pH of the mixture is adjusted to 5 by the portionwise addition of 27 g. of sodium bicarbonate. The mixture is filtered. The solid material is recrystallized from n-butanol. The product is 5-phenylpyrazinel; m.p. 208-210 C.

EXAMPLE ll p-Chlorophenylglyoxal hydrate is prepared in two steps from a-bromo-p-chloroacetophenone as described by Kornblum and Frazier [J. Am. Chem. Soc., 88, 865 1966)]. To the p-chlorophenylglyoxal hydrate (26.5 g., 0.14 mole) in ml. of methanol cooled to 30 is added, with stirring, glycinamide hydrochloride (15.7 g., 0.14 mole) in 130 ml. of methanol precooled to -30 C. To the stirring mixture is added dropwise 26 ml. of 12.5 N sodium hydroxide while the temperature is raised and is maintained at 5 to 0 C. for 2 hours. The mixture is then stirred at ambient temperature for 2 /2 hours. Concentrated hydrochloric acid (24 ml.) is added dropwise to the mixture with ice-bath cooling. This is followed by the portionwise addition of sodium bicarbonate (15 g.). The reaction mixture is refrigerated overnight, filtered and the solid is washed with water and recrystallized from 95 percent ethanol. The product is 5-( p-chlorophenyl )pyrazinol; m.p. 2l822l C.

EXAMPLE in bottle is cooled and the reaction solution is poured onto a stirred mixture of 700 g. of ice and 300 ml. of chloroform. After about 20 minutes, the mixture is cooled in an ice-salt bath and slowly neutralized with concentrated ammonium hydroxide, followed by the addition of 50% sodium hydroxide to make the mixture basic. The mixture is filtered through celite, the layers are separated, and the aqueous layer is extracted twice more with chloroform. The combined chloroform extracts are dried TNa SOQ and evaporated. The solid material is recrystallized from methanol. The product obtained is 2-chloro-5-phenylpyrazine; mp." 96-98 C.

EXAMPLE IV A sodium hydride-mineral oil suspension (54%. 28 g., 0.62 mole) is stirred with three ml. portions of dry hexane (Na- ,SO each portion being pipetted out to remove the mineral oil. Dimethylformamide (previously distilled and dried over a molecular sieve; ml.) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath and diethyl methylmalonate (99.5 g., 0.57 mole) is added dropwise to the stirred mixture. After addition is complete, the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. A solution of chloropyrazine (50 g., 0.44 mole) in dimethylformamide (50 ml.) is added dropwise. The mixture is then heated for 3 hours. raising the temperature during this 7 period to 120 C.

The reaction mixture is cooled to about 70 C. and water (20 ml.) is added. The mixture is concentrated to a small volume and the residual liquid is diluted with ice-water (300 ml.) and extracted several times with ether. The combined ether extracts are washed with hydrochloric acid, then with water, dried, and evaporated. The resulting liquid is distilled. The product obtained is diethyl a-methylpyrazinylmalonate; b.p. l14-118 C. (0.5 mm).

EXAMPLE V A sodium hydride-mineral oil suspension (54%; 3.1 g., 0.069 mole) is stirred with three 50 ml. portions of dry hexane, each portion being pipetted out to remove the mineral oil. Dimethylformamide (30 ml., previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath while diethyl mcthylmalonate (12 g., 0.069 mole) is added dropwise to the stirred mixture. After the addition is complete. the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. To the mixture is added dropwise 2-chloro-S-phenylpyrazine g., 0.053 mole) in warm dimethylformamide (55 ml.). After this addition is complete, the mixture is heated for 3 /2 hours during which time the temperature is raised to 120 C. The reaction mixture is cooled to about 80 C. and water (4 ml.) is added. The mixture is concentrated to a small volume, and the residual liquid is diluted with 50 g. of ice and extracted with ether several times. The combined ether extracts are washed with 5% hydrqchloric acid, then with water, and then dried and evaporated. The resulting oil is chromatographed on a; column of 500 g. of Merck acid-washed alumina. Elution with benzene-hexane (4:1) through ethyl acetate-benzene 1:3) yielded diethyl oz-methyl-S- phenylpyrazinylmalonate.

EXAMPLE vi A mixture of diethyl a-methyl-S-pheny1pyrazinylmalonate (10.3 g., 0.031 mole) and sodium cyanide (3.2 g., 0.065 mole) in dimethyl sulfoxide (120 mlr) is stirred and heated at 130 C. for hour. The reaction mixture is poured onto 300 g. of ice saturated with sodium chloride, and extracted several times with ether: The combined ether extracts are washed with water, dried, and eyaporated. The resulting material is triturated with warm hexaneand filtered. The hexane filtrate is evaporated and the resulting oil is distilled. The third fraction, which solidifies, is recrystallized from pentane and filtered at dry ice temperature. The product obtained is ethyl a-methyl-S-phenylpyrazii1- eacetate; m.p. 3840 C.

" EXAMPLE V11 A mixture ofdiethyl amethylpyrazinylmalonate, g., 0.08 mole) and sodium cyanide (8 g., 0.16 mole) in dimethyl sulfoxide 150 ml.) is stirred and heated between 125160 C. for 1 hour. The reaction mixture is poured into 400 ml. of ice water saturated with sodium chloride, and the mixture is extracted several times with ether. The ether extracts are combined and washed with water until neutral. dried, and evaporated. The resulting liquid is distilled. The product obtained is ethyl oz-methylpyrazineacetate; b.p. 71-73 C. (0.4 mm.

EXAMPLE V111 A mixture of diethyl a-methylpyrazinylmalonate (20 g., 0.08 mole), in 50% sodium hydroxide (40 m1.) is stirred and refluxed for 1% hours. The solution is cooled to room temperature, washed with ether, acidified, saturated with sodium chloride, and extracted several times with ether. The combined ether extracts are dried and evaporated. The solid material is recrystallized by dissolving in warm benzene with temperature below 50 C.) and then concentrating the solution under a stream of nitrogen with temperature below 50 C. The resulting mixture is filtered. The product obtained is a-methylpyrazineacetic acid; m.p. 95-96 C. dec.

EXAMPLE 1X A mixture of ethyl a-methyl-5-phenylpyrazineacetate (1.0 g., 0.0039 mole), water (8 ml.), and 50% aqueous sodium hydroxide (2 ml.) is refluxed for hour. The reaction solution is cooled to room temperature and diluted with water. The solution is washed three times with ether, chilled in an ice-bath, rendered acidic with concentrated hydrochloric acid, and filtered. The solid material is recrystallized from benzene-hexane (temperature kept below C.). The product obtained is a-methyl-5-phenylpyrazineacetic acid; m.p. l05-107 C. dec.

EXAMPLE X Concentrated ammonium hydroxide ml.) added to ethyl oz-methylpyrazineacetate (8.0 g., 0.044 mole) at ice-bath temperature. The mixture is stirred at room temperature for 2 hours, and then is saturated with sodium chloride and extracted with chloroform several times. The combined chloroform extracts are dried and evaporated. The solid material is recrystallized from ethyl acetate. The product obtained is a-methylpyrazineacetamide; m.p. 9698 C.

EXAMPLE X1 A mixture of ethyl a-methyl-5-phenylpyrazineacetate 5.0 g., 0.02 mole) and concentrated ammonium hydioxide 100 ml.) is stirred at room, temperature for 3 days in a stoppered flask/The reaction mixture is chilled and filtered. The solid material is recrystallized from benzene. The product obtained is a-methyl-S- phenyl-pyrazineacetamide; m.p. l52-l 54.

EXAMPLE X11 A 12 g. (0.058 mole) sample of 5-(p-chlorophenyl)- pyrazinol is added to phosphorous oxychloride (40 ml. containing sulfuric acid (3 drops) in a pressure bottle. The mixture is swirled briefly and heated in the open bottle at C. for [2 hour to allow the evolution of hydrogen chloride. The bottle is closed and heated at about C. for 4 hours. The bottle is cooled and the contents are poured onto a stirred mixture of 370 ml. of ice-water and 200 ml. of chloroform. The mixture .is chilled and slowly neutralized with concentrated ammonium hydroxide; a sufficient quantity of 50% sodium hydroxide is added to render the mixture basic. The mixture is filtered through celite, the layers separated. and the aqueous layer is extracted twice more with T chloroform. The combined chloroform extracts are dried and evaporated. The solid material is recr vstal 5(p-chlorophenyl)pyrazine; m.p. l45146 C.

9 EXAMPLE Xlll A sodium hydride-mineral oil suspension (54%; 1.8. g., 0.04 mole) is stirred with three 25 ml. portions of dry hexane, each portion being pipetted out to remove the mineral oil. Dimethylformamide (30 ml., previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath and diethyl methylmalonate (7 g., 0.04 mole) is added dropwise to the stirred mixture. After the addition is complete, the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. A solution of 2-ch1oro-5-(p-chloropheny1)pyrazine (8 g., 0.0355 mole) in warm dimethylformamide (70 ml.) is added dropwise. After this addition is complete, the mixture is heated for 3 hours during which time the temperature is raised to 120 C.

The reaction mixture is cooled to 80 C. and water (3 ml.) is added. The mixture is concentrated to a small volume. The residual liquid is diluted with 40 ml. of ice-water and extracted with ether several times. The combind ether extracts are washed with hydrochloric acid, then with water, dried, and evaporated. The solid material is recrystallized from hexane. The product obtained is diethyl 5-(p-chlorophenyl)-a-methylpyrazinylmalonate; m.p. 6264 C.

EXAMPLE XlV A mixture of diethyl 5-(p-chlorophenyl)-a-methylpyrazinylmalonate (7.0 g., 0.019 mole) and sodium cyanide (2.0 g., 0.04 mole) in dimethyl sulfoxide (60 ml.) is stirred and heated at 120 C. for /2 hour. The reaction mixture is poured into 200 ml. of ice-water saturated with sodium chloride. The material is extracted several times with ether. The combined ether extracts are washed with water, dried, and evaporated. The crude product is chromatographed on a column of acid washed alumina. Elution with benzene-hexane (1:4 through 4:1 followed by benzene is undertaken. The solid material is recrystallized twice from pentane. The product obtained is ethyl 5-(p-ch1orophenyl)-amethylpyrazineacetate; m.p. 4749 C.

EXAMPLE XV A mixture of ethyl 5-(p-ch1oropheny1)-oz-methylpyrazineacetate (2.33 g., 0.0080 mole), water (24 m1.), and 50% aqueous sodium hydroxide (6 ml.) is refluxed for 1% hours. The reaction mixture is diluted with about 30 ml. of water, washed three times with ether, chilled in an ice-bath, and then acidified with concentrated hydrochloric acid. The solid material is filtered and recrystallized from benzene-hexane (temperature kept below 50 C.). The product obtained is S-(p-chlorophenyl) a-methylpyrazineacetic acid; m.p. 111-112 v C. dec.

EXAMPLE XVl A mixture of ethyl 5-(p-chloropheny1)-a-methylpyrazineacetate (0.90 g., 0.0031 mole) and concentrated ammonium hydroxide (50 ml.) is stirred in a stoppered flask for 3 days at room temperature. The reaction mixture is chilled and filtered. Thesolid material is recrystallized from benzene. The product obtained is 5-(p-chlorophenyl)-a-mehtylpyrazineacetamide; m.p.

10 EXAMPLE XVll A solution of ethyl a-methyl-5-phenylpyrazineacetate, (3.0 g.. 0.0l2 mole) in ether (30 ml.) is added to a stirred solution of sodium amide (0.5. 0.013 mole) in liquid ammonia (50 ml.) at dry ice-acetone temperature. The mixture is allowed to reflux for A hour. Methyl iodide (1.7 g., 0.012 mole) is added. The mixture is stirred for 1 hour. The ammonia is allowed to evaporate. The residue is diluted with ether. Ammonium chloride is added until the mixture is neutral. The mixture is poured into dilute hydrochloric acid. The other layer is separated and washed successively with sodium bisulfite solution, sodium bicarbonate solution, and water. The ether solution is dried and evaporated. The solid material is recrystallized from pentane. The product obtained is ethyl a-dimethyl-5-phenylpyrazineacetate.

EXAMPLE XVlll Using the procedure of Example X1 and replacing ethyl a-methyl-5-phenylpyrazineacetate with an equivalent amount of ethyl a,a-dimethyl-5-pheny1pyrazineacetate, the product obtained is a,crdimethyl-5- phenylpyrazineacetamide.

EXAMPLE XIX Using the procedure of Example IX and replacing ethyl a-methyl-S-phenylpyrazineacetate with an equivalent amount of ethyl cad-dimethyl-S-phenylpyrazineacetate, the product obtained is a,a-dimethyl-5-phenyl-pyrazineacetic acid.

EXAMPLE XX A mixture of ethyl a-methyl-5-phenylpyrazineacetate (3.0 g., 0.012 mole), benzylamine (10 ml.) and powdered ammonium chloride (0.3 g.) is heated on the steam bath for 1 hour. The reaction mixture is washed with water, the water decanted, and the solid residue recrystallized from benzene or from ethanol. The product obtained is a-methyl-S-phenylpyrazine-N-benzylacetamide.

EXAMPLE XXI A mixture of a-methyl-S-phenylpyrazineacetic acid (3.0 g., 0.013 mole) and thionyl chloride (30 ml.) is stirred and warmed at about for V2 hour. The reaction solution is cooled in an ice-bath. A solution of morpholine (1.2 g., 0.014 mole) in benzene ml.) is added. The mixture is warmed on the steam bath for A hour, cooled. and diluted with water. The aqueous mixture is extracted several times with ether. The combined ether extracts are washed with dilute hydrochloric acid. dilute sodium bicarbonate, and water. and then dried and evaporated. The solid residue is recrystallized from benzene. The product obtained is 4-(dmethyl-5- phenylpyrazineacetyl )morpholine.

EXAMPLE XXll 3-Hydroxy-5-phenylpyrazine-2-carboxamide is prepared by the method of Dick, Wood and Logan. J. Chem. Soc.. 2131 (1956). The carboxamide is converted to 6-phenylpyrazino1 by the method of Jezo and Luzak. Chem. Zvest, 22, 190 1968 using percent sulfuric acid at C. Using the procedure of Exam ple 111 and replacing S-phenylpyrazinol with an equivalent amount of o-phenylpyrazinol. the product obtained is 2-chloro-6-phenylpyrazine. Using the procedure of Example V and replacing 2-chloro-5-phenylpyrazine with an equivalent amount of 2-chloro-6- phenylpyrazine, the product obtained is diethyl amethyl-6-phenylpyrazinylmalonate. Using the procedure of Example VI and replacing diethyl a-methyl-S- phenylpyrazinylmalonate with an equivalent amount of diethyl a-methyl-6-phenylpyrazinylmalonate, the product obtained is ethyl a-methyl-6-phenylpyrazineacetate. Using the procedure of Example IX and replacing ethyl a-methyl-S-phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-6-phenylpyrazineacetate, the product obtained is oz-methyl-o-phenylpyrazineacetic acid. Using the procedure of Example Xl and replacing ethyl oz-methyl-S -phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-- phenylpyrazineacetate, the product obtained is amethyl-6-phenylpyrazineacetamide.

EXAMPLE XXllI p-Chlorophenylglyoxal hydrate is treated with an aqueous sodium bisulfite solution. The mixture is then heated with an equimolar portion of aminomalonamide dissolved in water. The product obtained is 3-hydroxy- 5-(p-chlorophenyl)pyrazine-Z-carboxamide. The carboxamide is heated at 180 C. in 80 percent sulfuric acid. The product obtained is 6-(p-chlorophenyl)- pyrazinol. Using the procedure of Example ill and replacing S-phenylpyrazinol with an equivalent amount of 6-(p-chlorophenyl)-pyrazinol, the product obtained is 2-chloro-6-(p-chlorophenyl)pyrazine. Using the procedure of Example V and replacing 2-ehl oro-5 -phenylpyrazine with an equivalent amount of 2-chloro-6(pchlorophenyhpyrazine, the product obtained is diethyl a-methyl-6-( p-chlorophenyl )pyrazinylmalonate. Using the procedure of Example Vl andreplacing diethyl a-methyl-5-phenylpyrazinylmalonate with an equivalent amount of diethyl a-methyl-6-(p-chlorophenyl)- pyrazinylmalonate, the product'obtained is ethyl amethyl-o-(p-ehlorophenyl)pyrazineacetate. Using the procedure of Example IX and replacing ethyl a-methyl- S-phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-6-( p-chlorophenyl )-pyrazineacetate, the product obtained is u-methyl-6-(p-chlorophenyl)- pyrazineacetic acid. Using the, procedure of Example XI and replacing ethyl a-methyl-5-phenylpyra2ineacetate with an equivalent amount of ethyl a-methyl-fi-(pchlorophenyl)pyrazineacetate, the product obtained is a-methyl-6-( p-chlorophenyl )pyrazineacetamide.

i EXAMPLE XXIV Using the procedure of Example V and replacing Z-chloro-S-phenylpyrazine with an equivalent amount of Z-chloro-3-phenylpyrazine (prepared by the method of Karmas and Spoerri, J. Am. Chem. Soc.. 78, 4071. 1956). the product obtained is diethyl a-methyl-Iiphenylpyrazinylmalonate. Using the procedure of Example Vl and replacing diethyl d=methyl-5-phenylpyrazinylmalonate with an equivalent amount of diethyl a=methyl=3 phenylpyrazinylmalonate. the product obtained is ethyl a=methyl=3=phenylpyrazineacetate. Using the procedure of Example IX and replacing ethyl a=methyl=5=phenylpyrazineacetate with an equivalent amount of ethyl oz=methyl=3=phenylpyrazineace= tate. the product obtained is a=methyl=3=phenyl= pyrozineacetic acid. Using the procedure of Example Xi and replacing ethyl a=methyl=5=phenylpyrazineace= tote with an equivalent amount of ethyl a=methyl=3= phenylpyrazineacetate, the product obtained is w methyl-3-phenylpyrazineacetamide.

EXAMPLE XXV 2-Chloro-3-(p-chlorophenyl)pyrazine is prepared by the method of Karmas and Spoerri (loc. cit), using 3-(p-chlorophenyl)pyrazinol as the starting material. Starting with this material and using the procedures of Examples V, VI, IX, and XI, the products obtained are diethyl a-methyl-3-(p-chlorophenyl)pyrazinylmalonate, ethyl a-methyl-3-(p-chlorophenyl)pyrazineacetate, a-methyl-3-(p-chlorophenyl)pyrazineacetic acid, and a-methyl-3-(p-chlorophenyl )pyrazineacetamide.

EXAMPLE XXVI a-Bromocyclohexane acetyl bromide is prepared by the Hell-Volhard-Zelinsky reaction (Hell, Ber., 14, 891, l88l; Zelinsky. Ber., 20, 2026, 1887; Volhard, Ann., 242, 141, 1887) starting with cyclohexylacetic acid. The a-bromocyclohexane acetyl bromide is reacted with ammonia to product a-aminocyclohexylacetamide. Equimolecular portions of 30 percent aqueous glyoxal and a-aminocylclohexylacetamide are dissolved in aqueous methanol, and the mixture is treated with sodium hydroxide in the cold. The product obtained is 3-cyclohexylpyrazinol. Starting with this product and using the procedures of Examples [[1, V, VI, IX, andXl, the products obtained are 2-chloro-3- cyclohexylpyrazine, diethyl a-methyl-3-cyclohexylpyrazinylmalonate, ethyl oz-methyl-3-cyclohexylpyrazineacetate, a-methyl-3-cyclohexylpyrazineacetic acid, and oz-methyl-3-cyclohexylpyrazineacetamide.

EXAMPLE XXVlI ethyl a-methyl-6-cyclohexylpyrazineacetate, a-methyl-- 6-eyclohexylpyrazineacetic acid, and a-methyl-- cyclohexylpyrazineacetamide.

EXAMPLE XXVlll Using the procedure of Example I and replacing phenylglyoxal hydrate with an equivalent amount of cyclohyxylglyoxal hemihydrate, the product obtained is S-cyclohexylpyrazinol. Starting with this material and using the procedures of Examples lll. V, V]. IX, and Xl, the products obtained are 2-chloro-5-cyclohexylpyrazine, diethyl a-methyl=5-cyclohexylpyrazinylmalonate, ethyl a-methyl-5-cyclohexylpyrazineacetate, a-methyl-5-cyclohexylpyrazineacetic acid. and amethyl-5-cyclohexylpyrazineaeetamide.

EXAMPLE XXIX Using the procedure of Kornblum and Frazier, J. Am. Chem. Soc.. 88, 865 (1966), substituted phenylglyoxals, such as p=methylphenylglyoxaL p=methoxyphenyl= glyoxal, m=chlorophenylglyoxaL o=chlorophenyl= glyoxal. p=fluorophenylglyoxah 2.5=dichlorophenylglyoxal. p=trifluoromethylphenylglyoxal, 2,3=dimethyl= phenylglyoxal. and 2,3=dimethoxyphenylglyoxal, are

prepared from the corresponding substituted acetophenones. The substituted phenylglyoxals are used in the preparation of the corresponding S-(substitutedphenyl)pyrazinols by the procedure of Example II. The 2-chloro-5-( substituted-phenyl )pyrazines are prepared by the method of Example XII. The diethyl a-methyl-- (substituted-phenyl)pyrazinylmalonates are prepared by the method of Example XIII. The ethyl a-methyl-S- (substituted-phenyl)pyrazineacetates are prepared by the method of Example XIV. The a-methyl-5-(substituted-phenyl)pyrazineacetic acids are prepared by the method of Example XV. The amethyl-5-(substituted-phenyl )pyrazineacetamides are prepared by the method of Example XVI.

EXAMPLE XXX Using the procedure of Example XXIII and replacing p-chlorophenylglyoxal with substituted phenylglyoxals such as those identified in Example XXIX, the corresponding 6-(substituted-phenyl)pyrazinols are obtained. Correspondingly by the procedures of Examples XII, XIII. XIV, XV, and XVI, the corresponding 2'chloro-6-(substituted-phenyl)pyrazines, diethyl amethyl-6-'( substituted-phenyl )-pyrazinylmalonates, ethyl-a-methyl-6-( su bstitu ted-phenyl -pyrazineacetates, oz-methyl-6-(substituted-phenyl)pyrazineacetic acids, and a-methyl-6-(substituted-phenyl)- pyrazineacetamides are obtained.

EXAMPLE XXXI Using the procedure of Karmas and Spoerri (J. Am. Chem. Soc., 78, 4071, I956), and'starting with pyrazinol and substituted phenyldiazonium chlorides, such as p-methylphenyldiazonium chloride, p-methoxyphenyldiazonium chloride, n'i-chlorophenyldiazohium chloride, o-chlorophenyldiazonium chloride, p-fluorophenyldiazonium chloride, 2,5-dichlorophenyldiazonium chloride, p-trifluoromethylphenyldiazoniurn chloride, 2,3-dimethylphenyldiazoniun1 chloride, and 2,3-dimethoxyphenyldiazonium chloride, the corre sponding 3-(substituted-phenyl)pyraziriols are prepared. Starting with these materials and using the procedur'es of Examples XII, XIII, XIV, XV, and XVI, the products obtained are the corresponding 2-chloro-3- (substituted-phenyl)pyrazines, diethyl a-methyl-3- (substituted-phenyl)pyrazinylnialonates, ethyl a-methyl-3-(substituted-phenyl)pyrazineacetates, a-methyl-3- (substituted-ph'enyl)pyrazineacetic acids, and oz-met'hyl-3-(substituted-phenyl )pyrazineacetamides'.

/ EXAMPLE xxxn Using the procedure of Example XXI and replacing morpholine with an equivalent amount respectively of methylamine, dimethylamine, ethylamirie, diethylamine, is'opropylamine, and n-butylamine, the corresponding N-methyL, N,N-dimethyI-, N'ethyl-, N,N- diethyl-, N-iso'propyland N-n-butyl-acetamides are obtained. Repeating this procedure and replacing amethyl-S-phenyIpyraZineacetic acid with equivalent amounts of a-methyl-6-phenylpyrazineacetic acid and amethyl-3 -phenylpyrazineacetic acid, the correspond ing N-substituted amides of these compounds are ob tained.

EXAMPLE XXXIII Using the procedure of Example IV, replacing diethyl methylmalo'nate with an equivalent amount of diethyl malonate and replacing chloropyrazine with equivalent EXAMPLE XXXIV Using the procedure of Example IV, replacing diethyl methylmalonate with an equivalent amount of diethyl malonate; the product obtained is diethyl pyrazinylmalonate. Starting with this material and using the procedures of Examples VI and IX the products obtained are ethyl pyrazineacetate and pyrazineacetic a'cid.

EXAMPLE XXXV Using the procedures of Example XVII and replacing methyl iodide with equivalent amounts of ethyl iodide, i sopropyl iodide, and n-butyl iodide, the products obtained are ethyl a-methyI-a-ethyl S-phenylpyrazineacetate, ethyl a-methyl-a-isopropyl-5-phenylpyrazineacetate, and ethyl a-methyl-a-(n-butyl) 5-phenylpyrazineacetat e.

EXAMPLEIXXXVI Using the procedure of Example IX and replacing ethyl a-methyl-5-phenylpyrazineacetate, with equivalent amounts of the products of Example XXXV, the products obtained are a methyl-a-ethyl-S-phenylpyrazineacetic .acid, a-methyl-misoprdpyl-S-phenylpyra zineacetic acid and a-methyl-a-(n-butyU-5- phenylpyra-zineacetic acid.

EXAMPLE XXXVII Using the procedure of Example XI and replacing ethyl a-metliyl-S-phnylpyrazineacetate with equivalent amounts of the products of Example XXXV, the products obtained are a-methyl-a-ethyl-S-phenylpyrazineacetamide, a-methyl-aisopropyl-5-phenylpyrazineacetamide, and a-methyl-a-( n-butyl )-5- phenylpyrazineacetamide.

EXAMPLE xxxvm Using the procedure of Example V, employing 2- chloro-R-pyrazines having the formula wherein R has the same value as in Formula I hereinabove, and replacing diethyl methylmalonate with equivalent amounts of diethyl ethylmalonate, diethyl isopropylmalonate, and diethyl n-butylmalonate, the products obtained are diethyl a-substituted-R- pyrazinylmalonates having 'tie formula l c co c u R l EXAMPLE XXXlX Using the procedure of Example XVII, employing the ethyl a-substitutedR-pyrazineacetates of Example XXXVlll, and replacing methyl iodide with equivalent amounts of ethyl iodide, isopropyl iodide, and n-butyl iodide, the products obtained are the ethyl or, ai -disubstituted-R-pyrazineacetates having the structural wherein R has the same value as in Formula 1 hereinabove and wherein a and at are the following:

ethyl ethyl isopropyl ethyl n-butyl ethyl isopropyl isopropyl isopropyl n-butyl n-hutyl n-hutyl The corresponding (1', a -disubstituted-R-pyrazineacetic acids are prepared by the method of Example lX. The corresponding (1, cfldisubstituted-R- pyrazineacetamides are prepared by the method of Example Xl.

EXAMPLE XL Sodium hydride (547r in mineral oil; 6.1 g., 0.14 mole) is stirred with three portions (60 ml.) of dry hexane. each portion being pipetted out to remove the mineral oil. Dimethylformamide (previously distilled and dried over a molecular sieve; 55 ml.) is added through a pressure-equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is placed in an ice-bath and diethyl methylmalonate (24 g. 0.14 mole) is added dropwise to the stirred mixture. After the addition is complete, the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. A solution of -chloro-2.3- diphenylpyrazine (28 g.. 0.1 1 mole) in warm dimethylformamide 1 ml.) is added dropwise. The mixture is heated for 3 /2 hours while the temperature is raised to 120 C.

The reaction mixture is cooled to about 80 C. and water (8 ml.) is added. The mixture is concentrated to a small volume, and the residual liquid is mixed with 800 g. of ice and extracted several times with ether. The combined ether extracts are washed with 5% hydrochloric acid, then with water, dried, and evaporated. The resulting oil is chromatographed on a column of acid-washed alumina. Elution with benzenehexane (3:2 thru 100%.benzene) is undertaken. The produce obtained is diethyl a-methyl-5,6-diphenylpyrazinylmalonate.

EXAMPLE XLl A mixture of diethyl a-methyl-5,6-diphenylpyrazinylmalonate. (4.5 g.. 0.011 mole) and sodium cyanide (1.1 g., 0.023 mole) in dimethyl sulfoxide ml.) is

stirred and heated between l40-l65C. for 1 hour. The reaction mixture is poured onto 100 g. of ice, saturated with sodium chloride, and extracted several times with ether. The combined ether extracts are washed with water, dried, and evaporated. The resulting oil is purified by elution on a column of acid washed alumina with benzene-hexane (4:1 thru 100% benzene). The product obtained is ethyl oz-methyl-5,6- diphenylpyrazineacetate.

EXAMPLE XLlI Concentrated ammonium hydroxide (250 ml.) is added to a solution of ethyl a-methyl-S,6-diphenylpyrazineacetate (9.0 g., 0.027 mole) in absolute ethanol (250 ml.), and the mixture is stirred in a stoppered flask for 5 days. The mixture is kept at room tempera ture with occasional warming to 50 C. Additional concentrated ammonium hydroxide 100 ml.) is added to the stirring mixture on the fourth day. The stopper is removed, the mixture is diluted with another 100 ml. of concentrated ammonium hydroxide, and then warmed at 50 C. for 15 minutes. The mixture is chilled and filtered. The ammoniacal ethanol filtrate is diluted with a large volume of water. Sodium chloride is added, and the mixture is extracted several times with chloroform. The chloroform solution is dried and evaporated. The solid material is chromatographed on a column of 225 g. of acid washed alumina. Subsequent fractions are eluted with ethyl acetate and with ethyl acetatemethanol (9/1). The purest fraction is recrystallized from ethanol-water. The product obtained is a-methyl 5,o-diphenylpyrazineacetamide; m.p. 123-125 C.

EXAMPLE XLIIl A mixture of ethyl a-methyl-S,-diphenylpyrazineacetate (1.4 g., 0.004 mole), ethanol (20 ml.), water (3 ml.), and 50% sodium hydroxide (3 ml.) is

refluxed for 4 hours. The ethanol is evaporated and the EXAMPLE XLIV A mixture of diethyl a-methyl-S-pheny[pyrazinylmalonate (4 g. 0.012 mole) in water (32 ml.) containing 50% sodium hydroxide (8 ml.) is stirred and refluxed for 1 /4 hours. The solution is evaporated to about half 17 the original volume and chilled. The crystals formed are the disodium salt of a-methyl-S-phenylpyrazinylmalonic acid. Repeating the process but acidifying the solution after refluxing, and then adding sodium hydroxide, evaporating to half the original volume and chilling, the sodium salt of a-methyl-S-phenylpyrazineacetic acid is recovered. There procedures are repeated using ammonium hydroxide and calcium hydroxide respectively and adjusting the reflux time to obtain the corresponding ammonium and calcium salts of a-methyl--phenylpyrazinylmalonic acid and amethyl-5-phenylpyra.zineacetic acid. In a similar manner, the salts of the other malonic acids and acetic acids of this invention are prepared.

EXAMPLE XLV A quantity of a-methyl-5,6-diphenylpyrazineacetic acid is heated at about 130 C. for fifteen minutes. The resulting melt is diluted with water and extracted several times with ether. The ether solution is dried and evaporated. The solid material is recrystallized from 95 percent ethanol. The product obtained is 2,3-diphenyl- 5-ethylpyrazine; m.p. l02l()4 C.

EXAMPLE XLVI Using the procedures of Example XXVI and thereafter Examples 111, V, VI, IX, and XI as shown in Example XXVI, and replacing cyclohexylacetic acid with an equivalent amount of cyclopentylacetic acid, the products obtained are 3-cyclopentylpyrazinol, 2-chloro3- cyclopentylpyrazine, diethyl a-methyl3-cyclopentylpyrazinylmalonate, ethyl a-methyl-3-cyclopentylpyrazineacetic, oz-methyl-3-cyclopentylpyrazineacetic acid, and a-methyL3'cyclopentylpyrazineacetamide.

EXAMPLE XLVII Using the procedure of Example XXVII and thereafter Examples 111, V, VI, IX, and XI as shown in Example XXVII, and replacing cyclohexylglyoxal with an equivalent amount of cyclopentylglyoxal, the products obtained are -cyclopentylpyrazinol, 2-chloro-6- cyclopentylpyrazine, diethyl a-methyl-6-cyclopentylpyrazinylmalonate, ethyl a-methyl-o-cyclopentylpyrazineacetate, a-methyl-6-cyclopentylpyrazineacetic acid, and a-methyl-6-cyclopentylpyrazineacetamide.

EXAMPLE XLVIII Using the procedure of Example XXVIII and thereafter Examples 111, V, VI, IX, and X] as shown in Example XXVIII, and replacing cyclohexylglyoxal with an equivalent amount of cyclopentylglyoxal, the products obtained are 5-cyclopentylpyrazinol, 2-chloro-5- cyclopentylpyrazine, diethyl oz-methyl-5-cyclopentylpyrazinylmalonate, ethyl oz-methyl-S-cyclopentylpyrazineacetate, a-methyl-5-cyclopentylpyrazincacetic acid, and a-methyl-5-cyclopentylpyrazineacetamide.

EXAMPLE XLIX A mixture of diethyl ctr-ethyl-S-phenylpyrazinylmalonate 18 g., 0.053 mole), 4(1 ml. of 50 percent sodium hydroxide, and 160 ml. of water is refluxed for two hours. The mixture is then diluted with water, washed several times with ether, and acidified with cold concentrated hydrochloric acid. The solid material is recovered by filtration and crystallized from benzenehexane below 50 C. The product is a-ethyl-S-phenylpyrazineacetic acid; m.p. 909l C. dec.

EXAMPLE L Using the procedure of Example XL, replacing diethyl methylmalonate with an equivalent amount of diethyl ethylmalonate, the product obtained is diethyl a-ethyl-S,6-diphenylpyrazinylmalonate. Starting with this product and using the procedures of Examples XLl, XLIII, and XLII, the corresponding acetate, acetic acid, and acetamide are obtained.

Table I shows the ultraviolet light absorption characteristics of the compounds identified in the Examples. The solvent employed is methanol.

TABLE I Amax. Example No. (Mu) 6 IV 263 7,700 269* 6,500 306 1,100 V 251 15,400 288 14.500 VI 249 14.400 290 1 1,600 WI 265 7,000 270* 5.800 308 790 V111 267 6.700 272* 6,100

307 910 IX 24) 15,600 289 12,200 X 266 7,000 271* 6.300 309 970 X1 249 15.400 290 12.300 Xlll 255 18,600 287 19.200 305* 13.900 XIV 254 16,900 288 15,600 305* 11.800 XV 254 18,000 288 16,100 300* 13,000 XVI 254 17.600 288 16,300 300* 13.200 X1. 222 26,500 270* 11,700 283 1 2,100 310* 10.100 XI.I 220 22,800 267 1 1,000 293 l l .000 308* 10,000 XLII 220 23.400 265 1 1.500 292 1 1,300 310* 9.850 X1.V 219 20.200 263 10,400 295 10,100 310* 8.850 XLlIl 219 21.400 266 10.400 294 10.700 310* 9,300 XLIX 250 14.900 290 12.000

*shouldcr Certain of the novel compounds of this invention have been found to possess pharmacological activity as anti-inflammatory agents. These are identified by Example number in Table II. The test used is known as the kaolin-induced paw edema test. This test measures the ability of a compound, when administered in a single oral dose. to inhibit the swelling of the rat paw injected with a standard amount (0.1 ml.) of 10% kaolin suspension in saline. For comparative purposes, the activity of the compound to be tested is measured against that produced by the known antiinflammatory agent, phenylbutazone. In this assay, the test compound (0.49? suspension or 0.4% solution, depending on the compound) and phenylbutazone (0.4% solution) are administered in saline. Male Holtzman rats are used in the assay. The results are recorded in terms of percent inhibition produced by the compound and by phenylbutazone. The percent inhibition is calculated from the milliliters of mercury displaced as the edema develops in the paw. The paw is placed in a pool of mercury immediately after injection with the kaoline suspension, and a reading is taken on the quantity of mercury displaced. The animal is then returned to the cage, allowing the edema to develop. After 6 hours, the paw is again immersed in mercury and the quantity of mercury displaced is again measured. The method is described in J. Pharm. and Experimental Therapeutics, 162, 196-201 (1968).

Table ll-continued No. Dose (oral) Mg/Kg lnhihilion /1 Ex of Rats Ex. Phenylbutazone lzx. Phenylhutazone XLIX l0 I00 I00 2] 4l We claim:

1. A member selected from the group consisting of a compound of the formula 4. a-Methylpyrazineacetic acid.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3, 928, 31;? Page 1 of 2 DATED 1 December 23, 1975 V VENTOR(S) I Schwartz, Norman et a1 it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In Column 2, line 11, the word "heterocyclio" should read heterocyclic In Column 3, line 9, the word "are dloweralkylpyrazineacetate" should read and :L- loweralkylpyrazineacetate In Column 6, line 11, the word "B-phenylpyrazinel" should read 5-phenylpyrazinol In Column 8, line 5, the word '1 3/8 hrs should read l l/ i hrs.

In Column I i, line 33, the word "ethyl5" should read ethyl-5- r In Column 16, line 10, the word. "produce" should read product In Column 17, line 7', the word "There" should read These In Column 17', line 3 i, the word "pyrazineacetic" should read ----phrazineacetate Formulas:

In Column i, the word "Nah and DMF" shouldv read +Nah and DMF In Column "'1', Word "R1" Should read CHCOO CHCOOH In Column 4, the word "aralky amines" should read aralkyl amines UNITED STATES PATENT OFFICE Page 2 of 2 CERTIFICATE OF CORRECTION Patent 3,928,347 Dated December 23, 1975 Norman Schwartz et a1. Inventor s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

On the title page ABSTRACT, lines 1 and 2 "The compound,

2,3=diphenyle5=ethylpyrazine, useful as a precursor in the synthesis of those compounds" should read The compounds are Signed and Sealed this ninth Day Of August 1977 [SEAL] AUCSI.

RUTH C. MASON C. MARSHALL DANN Anesli'lg ff Commissioner of Patents and Trademarks 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 2. Diethyl Alpha -methylpyrazinylmalonate.
 3. Ethyl Alpha -methylpyrazineacetate.
 4. Alpha -Methylpyrazineacetic acid. 